Transplantation of allogeneic cells, tissues and organs is an evolving therapy that has become an increasingly attractive therapeutic option. The number of patients receiving transplants from unrelated donors is expected to double in the near future. Alloreactivity after transplantation has a major impact on clinical outcome, with pathological as well as beneficial effects. HLA mismatches are known to induce an immune reaction after transplantation, however the factors involved in predicting risk of unwanted immune reaction are not well understood.
Hematopoietic Stem Cell Transplantation (HSCT) is one example of a quickly growing therapeutic approach. The major limiting factor of HSCT remains the risk of graft-versus-host disease (GVHD), and since the number of patients receiving HSCT is expected to increase, the provision of novel approaches to prevent GVHD must be accelerated. To overcome the risk of GVHD, patients are preferably transplanted with a donor that is completely matched for all HLA-alleles. However, due to diversity of HLA molecules in the population, these completely matched donors are not available for approximately 40% of patients. When a completely matched donor is not available, a clinician often has to face the difficult decision to choose the best donor out of the mismatched donors (i.e. the one that carries the lowest GVHD risk).
Until now, determining which donor is most suitable relies on a laborious assay that requires up to 14 days of lab-work, for example the cytotoxic T-lymphocyte precursor frequency (CTLpf) assay. Functionally, better-permissible mismatches can be determined with the CTLpf assay. CTLpf scores of less than or equal to 1 per 106 PBL is associated with a better overall survival (Heemskerk et al (2007) Bone Marrow Transplantation, 40, 193-200). Despite such useful information able to be provided by laboratory methods, the time required for the analysis is prolonged and may lead to further detriment or death in patients in need of transplantation. Similar problems face clinicians before selecting transplantation material for cord blood or cord blood cell transplantations, kidney transplantations, or other transplantations at risk of side effects caused by unwanted alloreactivity. To find an alternative for the CTLpf assay, multiple, so far unsuccessful, attempts have been undertaken to predict non-permissible mismatches using two generally available prediction programs, HLAMatchmaker and HistoCheck.
HLAMatchmaker determines potential epitopes for antibodies and has proven its validity for solid-organ transplantation (Duquesnoy et al, Hum. Immunol. 2002; 63: 353-63; Duquesnoy et al, Transplantation 2003; 75: 884-89). HLAMatchmaker considers differences in amino-acid triplets as epitopes on HLA. Although antibodies potentially play a role in the development of GVHD, predictions based on HLAMatchmaker are not correlated to alloreactivity (Gupta et al, Blood 2010; 116: 1839-48).
HistoCheck is based on the concept of direct recognition of HLA disparities, that is, donor T cells recognize an intact mis-matched-HLA molecule loaded with a non-polymorphic peptide (Amir et al, Blood 2011; 118: 6733). HistoCheck determines the structural differences in HLA molecules in the peptide-binding grooves or regions contacting the T-cell receptor (Elsner et al, Bone Marrow Transplant. 2004; 33:165-69). By determining these structural differences, it aims to predict the likelihood of direct recognition of HLA disparities. Dissimilarity scores obtained with HistoCheck are also not correlated to alloreactivity (Spellman et al, Biol. Blood Marrow Transplant, 2011; Askar et al, Biol. Blood Marrow Transplant. 2011; 17: 1409-15).
In light of the previously existing techniques there exists a need for more reliable and faster methods for predicting whether donor material for a transplantation, which is HLA mismatched, is at increased risk of leading to a failed transplantation, for example development of GVHD, and/or an increase in mortality.